Fanconi Anemia (FA) is an autosomal recessive DNA repair disorder characterized by congenital abnormalities, cancer predisposition, and progressive bone marrow failure (BMF). FA is caused by biallelic mutations in one of sixteen FANC genes, the products of which cooperate in the FA/BRCA DNA repair pathway. Although the precise biochemical functions of the FA/BRCA pathway remain unclear, the pathway promotes homologous recombination (HR) repair. The FA/BRCA pathway also regulates cytokinesis, and pathway disruption results in increased binucleate bone marrow cells and apoptosis. FA cells are also uniquely hypersensitive to oxidative stress and apoptotic cytokines, such as IFNγ and TNFα.
BMF of FA patients is attributable to impaired stem cell pool. FA patients develop progressive bone marrow failure during childhood, and frequently require an allogeneic or unrelated donor bone marrow transplant. All blood lineages are deficient in FA patients suggests that the FA pathway regulates the function of hematopoietic stem and progenitor cells (HSPCs). CD34+ cells of FA patients, which are a human stem cell/progenitor cell enriched population, were not only lower in the number, but also exhibited compromised clonogenicity. Similarly, mice with Fanc mutations also displayed reduced numbers of hematopoietic stem cells (HSCs) with impaired reconstitution ability. In addition, the FA pathway also controls hematopoietic development. Knockdown of FANCA and FANCD2 in human embryonic stem cells impaired embryonic hematopoiesis which could be rescued by FA gene complementation. Therefore, these studies link FA pathway with stem cell function.
The mechanism of bone marrow failure in FA remains elusive. A need exist for a better understanding of the mechanism of BMF in FA as well as therapies to treat BMF other than bone marrow transplant.